Epigenetic proteins, such as histone methyltransferases represent important potential drug targets for indications like cancers, neurodegenerative disorders, and cardiovascular and metabolic diseases. At Reaction Biology Corporation (RBC), we are working toward the complete coverage of all epigenetic targets, including HMTs, to identify and improve epigenetic modulators that can be used in research and drug discovery. In this Phase II application, we have proposed three aims following successful Phase I studies to continue the understanding of HMTs' biological functions and as new drug targets. The aims include 1) Complete the screening of HMTs for identifying new probes and building the chemical-epigenetic data base; 2) Broader HTS and Structure-Activity Relationship (SAR) study to identify and increase the potency of NSD inhibitors; and 3) Evaluating NSD inhibitors' efficacy in cell based assays, and determining their kinetic MOAs and early DMPK/tox profiles. We'll meet the following milestones: (1) Develop and commercialize 10 or more HMT probes as general research tools for at least 5 HMTs; 2) Improve at least 2 lead compounds' potency into the nanomolar range against NSDs that have different structure scaffolds, with good cell based activity and DMPK profiles; and (3) we will be able to launch one of the largest publicly available chemical-epigenetic data bases built on the screening activities from the compound collections that include most of the FDA approved drugs, clinical trial agents, diversified libraries, and natural products.